Project Summary/Abstract The University of Minnesota has been highly committed to The BMT CTN. Our expertise on alternative donors and graft-vs-host disease served as the basis for successful Network studies. Our participation in the Network includes a past-Steering Committee chair, national PIs on six protocols, leading roles in Network publications and committing institutional resources to develop and successfully execute Network trials. Our proposal addresses the risk of acute myeloid leukemia (AML) relapse after reduced intensity allogeneic hematopoietic cell transplantation (HCT), which remains the main cause of treatment failure. Our institutions long-lasting interest on natural killer (NK) cell biology as a critical mediator of the graft-versus-tumor/leukemia (GVL) effect led to the development of this platform using ALT-803, a soluble complex consisting of two protein subunits of a human IL-15 variant associated with high affinity to a dimeric human IL-15 receptor ? (IL-15R?) sushi domain/human IgG1 Fc fusion protein enhancing NK cell specificity and half-life. Our hypothesis is that stimulating the innate immune system with ALT-803 will reduce the cumulative incidence of relapse and improved probability of relapse-free survival (RFS), after reduced intensity conditioning (RIC) HCT. In early clinical trial studies we demonstrated the safety and established side effect profile of ALT-803 when given to patients with advanced hematological malignancies, including post-allogeneic HCT. A phase 2 study on ALT-803 administration as maintenance after reduced intensity allogeneic HCT for AML and myelodysplastic syndrome is in the last steps of regulatory approval and will provide further data on the safety and feasibility of the post-transplantation maintenance approach. The primary objective of the proposed the phase 3 randomized placebo-controlled clinical trial in this proposal is to determine if ALT-803 improves the probability of disease-free survival as maintenance after reduced intensity allogeneic HCT for AML in first complete remission. The administration of immune modulatory agents such as ALT-803 aiming reducing the risk of relapse and improve outcomes after HCT is one of many potentially practice changing strategies that require confirmation on a multicenter randomized clinical trial, which is part of the BMT CTN mission. Our institution's continued commitment to the Network's success is not only reflected in developing new protocols, but alos continued internal process to better support regulatory, enrollment and sample collection requirements Network clinical trials.